CN103936710B - Piperonyl Pentadienamide derivatives that N-replaces and its preparation method and application - Google Patents
Piperonyl Pentadienamide derivatives that N-replaces and its preparation method and application Download PDFInfo
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Abstract
The invention discloses the piperonyl Pentadienamide derivatives of N-replacement or the salt of its pharmaceutical acceptable acid, as shown in the formula the compound shown in I (wherein, the definition of R refers to specification sheets), and comprise medicinal compositions or the healthcare products of the piperonyl Pentadienamide derivatives of this N-replacement or the salt of its pharmaceutical acceptable acid, also disclose the preparation method of the piperonyl Pentadienamide derivatives of N-replacement or the salt of its pharmaceutical acceptable acid simultaneously, and the application of the reducing blood-fat of the piperonyl Pentadienamide derivatives of N-replacement or the salt of its pharmaceutical acceptable acid, be included in preparation and reduce serum total cholesterol, reduce low density lipoprotein cholesterol, reduce triglyceride level and prevention high density lipoprotein cholesterol reduce medicine or healthcare products in application.
Description
Technical field
The invention belongs to medical art, more particularly, relate to the application of piperonyl Pentadienamide derivatives and preparation method thereof that N-replaces and reducing blood-fat.
Background technology
Hyperlipidemia is the primary Hazard Factor of atherosclerosis (AS).Cardiovascular disorder caused by AS currently jeopardizes one of principal disease of human health and life.Cardiovascular and cerebrovascular diseases has the advantages that sickness rate is high, disability rate is high, mortality ratio is high and recurrence rate is high.This kind of disease has become in the whole world " number one killer " of harm humans health.The sickness rate of domestic and international coronary heart disease, mortality ratio rise rapidly nearly decades, and in China, hyperlipidemia associated patient has reached about 200,000,000 crowds; Annual 7000 ten thousand people in the whole world die from the relative disease that hyperlipidemia causes.The coronary heart disease study on prevention that cardiopulmonary blood research institute of the U.S. carries out 7 years confirms, the application of hypolipidemic can reduce deaths from heart disease rate 24%, reduces non-lethality heart attack rate 19%.Hypolipidemic can delay or alleviate the development of AS pathology, and promotes that it disappears.For improving China to the prevention of hyperlipidemia and cardiovascular and cerebrovascular disease, treatment ability, research and develop the important goal that new lipopenicillinase medicinal compound and new drug have become China medical sci-tech worker.
Conventional chemical lipid lowerers has following several both at home and abroad: 1. Statins; 2. the special class of shellfish; 3. nicotinic acid class; 4. cholic acid chelating (resene) agent; 5. polyenoid class; Deng.External hypolipidemic research Main way: 1. study novel cholesterol absorption inhibitor, represents medicine for complying with pool for wheat (Ezetimibe, Zetia); 2. study cholesteryl ester acyltransferase (ACAT) inhibitor, this class medicine opens the treatment of hypercholesterolemia mechanism.3. study novel form and compound drug combination.Wherein have: coupling of lovastatin controlled release tablet, extended-release niacin preparation Nispan, microparticle fenofibrate capsule, the special class of shellfish and Statins etc.Chemicals research aspect while continually developing there is novel mechanism hypolipidemic, various can alleviate adverse drug reaction, the novel form heightened the effect of a treatment and compound preparation also sequential use in clinical, achieve good therapeutic action.
2002 start, Borijihan Geriletu, golden stake, Zhao Ruiguo, Bao Lanlan, Wu Yong, fiber crops spring outstanding person, Han Jingfen etc., a large amount of research work has been done to piperaceae plant Bi roots of grass ethanol extraction and derivative thereof, isolate enough piperonyl acid amides crude substance first: PPA (Piperlonguminine), C
16h
19nO
3, and large quantifier elimination has been carried out to it.The research successively carried out has: the research of PPA effective constituent (golden stake, rich Geril Tu, " whole nation biochemistry in 2004 and biotech drug Annual Conference ", " research of effective constituent dialled by reducing blood-fat anaesthetic bamboo or wicker fence ", 04.9.12-19, the North Sea.); (PPA is on the impact of hyperlipidemia rats blood lipid metabolism and related gene expression thereof on the research of the impact of hyperlipidemia rats blood lipid metabolism and related gene expression thereof for PPA; herbal medicine; in February, 2008; the fiber crops spring is outstanding; rich Geril Tu) and the mechanism of action (HypolipidemiceffectsofanewpiperinederivativeGB-NfromPipe rlonguminhigh-fatdiet-fedrats; PharmaceuticalBiology, 2012Aug; 50 (8): 962-7.) and pharmacokinetic etc.The chemical structural formula of PPA is as follows:
Found that PPA had good lipid-lowering effect by reference to former research.But because PPA is water-insoluble organism, therefore it has certain limitation as medicine, infer that piperonyl has good reducing blood lipid additionally by research in the past, therefore contriver's imagination synthesizes a kind of not only containing piperonyl but also compound soluble in water, be applied as medicine, its drug effect is observed, to obtain medicinal compound better with PPA, Simvastatin simultaneous test.
Summary of the invention
Contriver has found through lot of experiments the piperonyl Pentadienamide derivatives that a kind of N-replaces, and the existing piperonyl of this compound is as hydrophobic grouping, and again with hydrophilic radical, the salt of its pharmaceutical acceptable acid is soluble in water, is suitable as medicine; In addition, the present inventor also finds that this compound has excellent reducing blood lipid.
The object of this invention is to provide the piperonyl Pentadienamide derivatives of N-replacement or the salt of its pharmaceutical acceptable acid.
Second object of the present invention is to provide the medicinal compositions or protective foods that comprise the piperonyl Pentadienamide derivatives of N-replacement or the salt of its pharmaceutical acceptable acid.
3rd object of the present invention is to provide the preparation method of the piperonyl Pentadienamide derivatives of N-replacement or the salt of its pharmaceutical acceptable acid.
4th object of the present invention is to provide the reducing blood-fat application of the piperonyl Pentadienamide of N-replacement or the salt of its pharmaceutical acceptable acid.
In one embodiment of the present invention, the invention provides the piperonyl Pentadienamide derivatives of N-replacement or the salt of its pharmaceutical acceptable acid, as shown in the formula the compound shown in I
Here, R is the amino C1-C4 alkyl replaced.R is selected from amino methyl, the ethyl of amino replacement, the propyl group of amino replacement or the amino butyl replaced, here, the ethyl that described amino replaces is selected from 1-amino-ethyl or 2-amino-ethyl, the propyl group that described amino replaces is selected from 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 1-amino-2-propyl group, or 2-amino-2-propyl group, the butyl that described amino replaces is selected from 1-aminobutyl, 2-aminobutyl, 3-aminobutyl, 4-aminobutyl, 1-amino-2-butyl, 2-amino-2-butyl, 3-amino-2-butyl, 4-amino-2-butyl, 1-amino-2-methyl-propyl group, 2-amino-2-methyl-propyl group, 3-amino-2-methyl-propyl group, or 2-aminomethyl-2-propyl group, preferably, R is 2-amino-ethyl.
In embodiments of the invention, the salt of the piperonyl Pentadienamide derivatives that N-provided by the invention replaces or its pharmaceutical acceptable acid, wherein, the salt of described pharmaceutical acceptable acid is selected from hydrochloride, vitriol, phosphoric acid salt, hydrobromate, maleate, mesylate or benzene methanesulfonic acid salt, preferably, be hydrochloride.
In embodiments of the invention, the invention provides a kind of N-ethylenediamine base-piperonyl Pentadienamide hydrochloride, its chemical structure is:
On the other hand, the invention provides the medicinal compositions comprising the piperonyl Pentadienamide derivatives of N-replacement or the salt (compound such as formula shown in I) of its pharmaceutical acceptable acid or protective foods.Here, the route of administration of the medicinal compositions of the described piperonyl Pentadienamide derivatives of N-replacement or the salt of its pharmaceutical acceptable acid comprises oral administration or parenteral administration.The medicinal compositions of the salt of the piperonyl Pentadienamide derivatives that N-provided by the present invention replaces or its pharmaceutical acceptable acid or protective foods, except the piperonyl Pentadienamide derivatives of activeconstituents N-replacement or the salt of its pharmaceutical acceptable acid, also comprise further pharmaceutically or acceptable auxiliary material on protective foods.The oral drug preparation of the prepared one-tenth of salt of the piperonyl Pentadienamide derivatives that N-of the present invention replaces or its pharmaceutical acceptable acid, injection, protective foods can be prepared according to prior art, such as, " pharmaceutics " (the 6th edition) of Cui Defu chief editor, People's Health Publisher, in August, 2007, and liquid preparation (as oral liquid, injection liquid etc.), solid preparation (tablet, capsule etc.) can be prepared into.The consumption of salt every day of the piperonyl Pentadienamide derivatives that N-of the present invention replaces or its pharmaceutical acceptable acid can be 10mg to 5g, can adopt once a day, or every day the method for application of two to three times.
The third aspect, the invention provides the preparation method of the piperonyl Pentadienamide derivatives of N-replacement or the salt (compound such as formula shown in I) of its pharmaceutical acceptable acid, comprises the steps:
Comprise piperinic acid and SOCl
2occur acylation reaction, then with H
2n-R reacts thus obtains the compound shown in formula I.Here, the definition of radicals R is described above; The piperinic acid adopted, its source is see JingfenHan, GereltuBorjihan; Synthesisandanti-hyperlipidemicactivityofanovelstarchpip erinicester, CarbohydratePolymers, 11, July2007,7.
In a kind of preferred embodiment of the present invention, the preparation method of the salt of the piperonyl Pentadienamide derivatives that N-provided by the invention replaces or its pharmaceutical acceptable acid, wherein, piperinic acid is the piperonyl pentadiene acid esters of piperonyl pentadienoic acid (GB-H) or non-piperonyl pentadienoic acid, more preferably, be piperonyl pentadienoic acid (GB-H).
In a kind of preferred embodiment of the present invention, the preparation method of the salt of the piperonyl Pentadienamide derivatives that N-provided by the invention replaces or its pharmaceutical acceptable acid, wherein, piperinic acid and SOCl
2be dissolved in chloroparaffin and carry out acylation reaction, be then that solvent and acyl chlorides react with chloroparaffin, here, described chloroparaffin is preferably methylene dichloride.
In a kind of preferred embodiment of the present invention, the invention provides the preparation method of the piperonyl Pentadienamide derivatives of N-replacement or the salt of its pharmaceutical acceptable acid, piperonyl pentadienoic acid is dissolved in methylene dichloride, add DMF(N, dinethylformamide), reflux to 72 DEG C, adds SOCl
2reaction 1h, pours in eggplant-shape bottle by reacted solution, underpressure distillation, and removing organic solution, obtains drier pepper acyl chlorides (GB-C).(GB-C) is dissolved in CH
2cl
2, be slowly added drop-wise to H
2in N-R, reaction 0.5h, suction filtration, by filtrate with distilled water wash 3 times, removes excessive H
2n-R, then adds the pharmaceutically acceptable sour example hydrochloric acid of 1mol/L wherein, shakes up and makes its pH become acidity.By solution as in separating funnel, stratification.Obtain organic phase and aqueous phase respectively.In aqueous phase, drip NaOH solution, make it become alkalescence, after solid is separated out, use CH
2cl
2extraction, underpressure distillation, obtains faint yellow solid, dries product namely.
In a kind of preferred embodiment of the present invention, the invention provides the preparation method of the piperonyl Pentadienamide derivatives of N-replacement or the salt of its pharmaceutical acceptable acid, wherein, piperinic acid is the piperonyl pentadiene acid esters of piperonyl pentadienoic acid (GB-H) or non-piperonyl pentadienoic acid, more preferably, be piperonyl pentadienoic acid (GB-H).
In a kind of preferred embodiment of the present invention, the preparation method of the salt of the piperonyl Pentadienamide derivatives that N-provided by the invention replaces or its pharmaceutical acceptable acid, wherein, piperinic acid and SOCl
2be dissolved in methylene dichloride and carry out acylation reaction, reaction terminate after again with H
2n-R such as reacting ethylenediamine prepares the reaction of acid amides.
In a kind of preferred embodiment of the present invention, the preparation method of the salt of the piperonyl Pentadienamide derivatives that N-provided by the invention replaces or its pharmaceutical acceptable acid, piperonyl pentadienoic acid is dissolved in methylene dichloride, add DMF(N, dinethylformamide), reflux to 72 DEG C, adds SOCl
2reaction 1h, distills reacted solution decompression, and removing organic solution, obtains drier pepper acyl chlorides (GB-C).(GB-C) is dissolved in CH
2cl
2, be slowly added drop-wise to H
2in N-R such as quadrol, reaction 0.5h, suction filtration, by filtrate with distilled water wash 3 times, removes excessive H
2n-R is quadrol such as, then adds the pharmaceutically acceptable sour example hydrochloric acid of 1mol/L wherein, shakes up and makes its pH become acidity.By solution as in separating funnel, stratification.Obtain organic phase and aqueous phase respectively.By aqueous phase underpressure distillation, after solid is separated out, filtering drying, obtains orange/yellow solid, product GBCNH namely
3.
Fourth aspect, the application in blood lipid-lowering medicine prepared by the salt of the piperonyl Pentadienamide derivatives or its pharmaceutical acceptable acid that the invention provides N-replacement.
In one embodiment of the present invention, the salt of the piperonyl Pentadienamide derivatives or its pharmaceutical acceptable acid that the invention provides a kind of N-replacement reduces the application in the medicine of serum total cholesterol in preparation.
In one embodiment of the present invention, the salt of the piperonyl Pentadienamide derivatives or its pharmaceutical acceptable acid that the invention provides a kind of N-replacement reduces the application in the medicine of low density lipoprotein cholesterol in preparation.
In one embodiment of the present invention, the invention provides the piperonyl Pentadienamide derivatives of a kind of N-replacement or the application of the salt of its pharmaceutical acceptable acid in the medicine of preparation prevention high density lipoprotein cholesterol reduction.
In one embodiment of the present invention, the salt of the piperonyl Pentadienamide derivatives or its pharmaceutical acceptable acid that the invention provides a kind of N-replacement reduces the application in the medicine of triglyceride level in preparation.
In one embodiment of the present invention, the application in blood fat reducing health products prepared by the salt of the piperonyl Pentadienamide derivatives or its pharmaceutical acceptable acid that the invention provides a kind of N-replacement.
In one embodiment of the present invention, the salt of the piperonyl Pentadienamide derivatives or its pharmaceutical acceptable acid that the invention provides a kind of N-replacement reduces the application in the healthcare products of serum total cholesterol in preparation.
In one embodiment of the present invention, the salt of the piperonyl Pentadienamide derivatives or its pharmaceutical acceptable acid that the invention provides a kind of N-replacement reduces the application in the healthcare products of low density lipoprotein cholesterol in preparation.
In one embodiment of the present invention, the invention provides the piperonyl Pentadienamide derivatives of a kind of N-replacement or the application of the salt of its pharmaceutical acceptable acid in the healthcare products of preparation prevention high density lipoprotein cholesterol reduction.
In one embodiment of the present invention, the salt of the piperonyl Pentadienamide derivatives or its pharmaceutical acceptable acid that the invention provides a kind of N-replacement reduces the application in the healthcare products of triglyceride level in preparation.
The invention provides a kind of method of the disease that treatment is relevant to the blood fat raised in curee in need, comprise and use the piperonyl Pentadienamide derivatives of N-replacement of significant quantity or the medicine of the salt of its pharmaceutical acceptable acid to this curee.
The invention provides a kind of method of the disease that treatment is relevant to the serum total cholesterol raised in curee in need, comprise and use the piperonyl Pentadienamide derivatives of N-replacement of significant quantity or the medicine of the salt of its pharmaceutical acceptable acid to this curee.
The invention provides a kind of method of the disease that treatment is relevant to the low density lipoprotein cholesterol raised in curee in need, comprise and use the piperonyl Pentadienamide derivatives of N-replacement of significant quantity or the medicine of the salt of its pharmaceutical acceptable acid to this curee.
The invention provides a kind of in curee in need treatment and high density lipoprotein cholesterol reduce the method for relevant disease, comprise and use the piperonyl Pentadienamide derivatives of N-replacement of significant quantity or the medicine of the salt of its pharmaceutical acceptable acid to this curee.
The invention provides a kind of method of the disease that treatment is relevant to the triglyceride level raised in curee in need, comprise and use the piperonyl Pentadienamide derivatives of N-replacement of significant quantity or the medicine of the salt of its pharmaceutical acceptable acid to this curee.
The present invention is surprisingly found out that unforeseeable effect by test: salt significance in reduction serum total cholesterol, triglyceride level and low density lipoprotein cholesterol of the piperonyl Pentadienamide derivatives that N-replaces or its pharmaceutical acceptable acid is better than contrast medicine Simvastatin, and, be also better than piperonyl pentadienoic acid (2-methyI-oropvD) acid amides GB-N; And there is the effect improving high density lipoprotein cholesterol.Testing data shows, the salt of the piperonyl Pentadienamide derivatives that N-of the present invention replaces or its pharmaceutical acceptable acid has water-soluble preferably, and GB-N is then water insoluble.
Accompanying drawing explanation
The 500MHz of N-ethylenediamine base-piperonyl Pentadienamide prepared by embodiment 1 that what Fig. 1 represented is
1h-NMR spectrogram.
The 125MHz of N-ethylenediamine base-piperonyl Pentadienamide prepared by embodiment 1 that what Fig. 2 represented is
13c-NMR nuclear magnetic resonance map.
The MS collection of illustrative plates of N-ethylenediamine base-piperonyl Pentadienamide prepared by embodiment 1 that what Fig. 3 represented is.
The 500MHz of N-ethylenediamine base-piperonyl Pentadienamide hydrochloride prepared by embodiment 2 that what Fig. 4 represented is
1h-NMR spectrogram.
The 125MHz of N-ethylenediamine base-piperonyl Pentadienamide hydrochloride prepared by embodiment 2 that what Fig. 5 represented is
13c-NMR nuclear magnetic resonance map.
The MS collection of illustrative plates of N-ethylenediamine base-piperonyl Pentadienamide hydrochloride prepared by embodiment 2 that what Fig. 6 represented is.
What Fig. 7 represented is embodiment 3 pairs of rat serum total cholesterol level measurement results.
What Fig. 8 represented is embodiment 3 pairs of rat serum content of triglyceride measurement results.
What Fig. 9 represented is embodiment 3 pairs of rat serum low density lipoprotein cholesterol assay results.
What Figure 10 represented is embodiment 3 pairs of rat serum high density lipoprotein cholesterol assay results.
Note: in Fig. 7 to 10, zero represents pole significant difference; △ represents significant difference.
Embodiment
Below will make further detailed description the present invention by way of example, but following examples are only example, and are not used to limit the present invention.
Embodiment 1
The preparation method of N-ethylenediamine base-piperonyl Pentadienamide
Prepare before experiment: heavily steam SOCl
2, CH
2cl
2.Test solvent is anhydrous solvent, prevents itself and water generation side reaction.Take 10g piperonyl pentadienoic acid (GB-H) in 500ml round-bottomed flask, add 150mlCH
2cl
2and 1mlDMF, be heated to 72 DEG C; Then slowly in round-bottomed flask, SOCl is dripped
230ml, makes reaction carry out 1h under 73 DEG C of conditions; Reacted solution is carried out underpressure distillation, and removing organic solution, obtains drier pepper acyl chlorides (GB-C).
Pepper acyl chlorides (GB-C) is dissolved in CH
2cl
2, be slowly added drop-wise in 60ml quadrol, reaction 0.5h, suction filtration, by filtrate with distilled water wash 3 times, removes excessive quadrol, then adds the hydrochloric acid of 1mol/L wherein, make its pH become acidity.Solution is placed in separating funnel, stratification.Obtain organic phase and aqueous phase respectively.In aqueous phase, drip NaOH solution, make it become alkalescence, after solid is separated out, use CH
2cl
2extraction, underpressure distillation, obtains faint yellow solid, dries product N-ethylenediamine base-piperonyl Pentadienamide (GBCNH) namely.
The molecular formula C of GBCNH
14h
16o
3n
2, ESI-MSm/z:260.89 [M+H]
+.Concrete reaction conditions is as follows:
The structure of N-ethylenediamine base-piperonyl Pentadienamide is determined
500MHz Brooker nuclear magnetic resonance analyser, solvent deuterated dimethyl sulfoxide, measures the 500MHz of N-ethylenediamine base-piperonyl Pentadienamide
1h-NMR spectrogram (see figure 1); N-ethylenediamine base-piperonyl Pentadienamide 125MHz
13c-NMR nuclear magnetic resonance map (see figure 2).
N-ethylenediamine base-piperonyl Pentadienamide
1h-NMR spectrogram chemical shift data table, unit ppm
N-ethylenediamine base-piperonyl Pentadienamide
13c-NMR spectrogram chemical shift data table, unit ppm
Embodiment 2
The preparation method of N-ethylenediamine base-piperonyl Pentadienamide hydrochloride
Prepare before experiment: heavily steam SOCl
2, CH
2cl
2.Test solvent is anhydrous solvent, prevents itself and water generation side reaction.Take 10g piperonyl pentadienoic acid (GB-H) in 500ml round-bottomed flask, add 150mlCH
2cl
2and 1mlDMF, be heated to 72 DEG C; Then slowly in round-bottomed flask, SOCl is dripped
230ml, makes reaction carry out 1h under 73 DEG C of conditions; Reacted solution is carried out underpressure distillation, and removing organic solution, obtains drier pepper acyl chlorides (GB-C).
Pepper acyl chlorides (GB-C) is dissolved in CH
2cl
2in, slowly in instillation 60ml quadrol, reaction 0.5h, suction filtration, by filtrate with distilled water wash 3 times, removes excessive quadrol, then adds the hydrochloric acid of 1mol/L wherein, make its pH become acidity.By solution as in separating funnel, stratification.Obtain organic phase and aqueous phase respectively.By aqueous phase underpressure distillation, except anhydrating, obtaining orange/yellow solid, drying product N-ethylenediamine base-piperonyl Pentadienamide hydrochloride (GBCNH3) namely.
The molecular formula C of GBCNH3
14h
16o
3n
2hCl, ESI-MSm/z:261.04 [M+H]
+.Concrete reaction conditions is as follows:
The structure of N-ethylenediamine base-piperonyl Pentadienamide hydrochloride is determined
500MHz Brooker nuclear magnetic resonance analyser, solvent deuterated dimethyl sulfoxide, measures the 500MHz of N-ethylenediamine base-piperonyl Pentadienamide hydrochloride
1h-NMR spectrogram (see figure 4); N-ethylenediamine base-piperonyl Pentadienamide hydrochloride 125MHz
13c-NMR nuclear magnetic resonance map (see figure 5).
N-ethylenediamine base-piperonyl Pentadienamide hydrochloride
1h-NMR spectrogram chemical shift data table, unit ppm
N-ethylenediamine base-piperonyl Pentadienamide hydrochloride
13c-NMR spectrogram chemical shift data table, unit ppm
Embodiment 3
N-ethylenediamine base-piperonyl Pentadienamide hydrochloride rat therapeutic reducing blood-fat comparative efficacy test
(1) experiment material
Experiment reagent: piperonyl pentadienoic acid (2-methyl-propan base) acid amides (GB-N), N-ethylenediamine base-piperonyl Pentadienamide hydrochloride University of the Inner Mongol preparation;
Simvastatin (SVTT) is produced by Guangdong Bi Di medicine company limited-liability company; Product batch number: 20120702
Total cholesterol test kit, is produced by Zhongsheng Beikong Biological Science & Technology Co., Ltd.; Lot identification mark: 121841, production licence number: capital medicine prison tool is produced and permitted 20000271
Triglyceride Reagent box, is produced by Zhongsheng Beikong Biological Science & Technology Co., Ltd.; Product batch number: 120921, production licence number: capital medicine prison tool is produced and permitted 20000271
High density lipoprotein cholesterol test kit, is produced by Zhongsheng Beikong Biological Science & Technology Co., Ltd.; Product batch number: 120441, production licence number: capital medicine prison tool is produced and permitted 20000271
Low density lipoprotein cholesterol test kit, is produced by Zhongsheng Beikong Biological Science & Technology Co., Ltd.; Product batch number: 120471, production licence number: capital medicine prison tool is produced and permitted 20000271
Cholesterol is produced by Beijing bispin microbiological culture media products factory; Product batch number: 20120619
Sodium cholic acid is produced by Beijing bispin microbiological culture media products factory; Product batch number: 20120525
Laboratory apparatus: PRONTOEVOLUTION full automatic biochemical apparatus (Italy produces); TDL-5 whizzer (Anting Scientific Instrument Factory, Shanghai);
Laboratory animal: Wistar male white rat, purchases from Beijing Vital River Experimental Animals Technology Co., Ltd..
High lipid food is filled a prescription: cholesterol 3%, lard 10%, Sodium cholic acid 0.5%, and basal feed 86.5%(fills a prescription: flour 17.14%, ground rice 8.57%, corn 17.14%, wheat bran 21%, fish meal 1.71%, salt 0.857%, VITAMIN 0.085%, beans material 17.14%)
(2) experimental technique
Get Wistar big white mouse 72, body weight 170 ± 10g, male, be divided into 6 groups at random by body weight and number, often organizing 12.Under experimental situation, rat common standard feed of feeding observes 7 days, gets tail blood, and measure serum total cholesterol (TC), measurement result is in table 1.According to serum total cholesterol (TC) level, each group data show indices all within normal range.From the 8th day, if the Ith group is blank group, common standard of feeding feed.All the other each group of high lipid foods of feeding, continuous eight days, get tail blood next day, measure TC, measurement result is in table 2, and data show that index mean value is all higher than normal value, the P value that each group of hyperlipidemia model value compares with normal value is all less than 0.05, so, judge that hyperlipemia model is successfully prepared.Again according to TC level, be divided into 6 groups at random in table 3, often organize 10 (rat of 12 blood fat model differences is discarded), continue high lipid food of feeding.II group is high lipid food model control group, and III group is Simvastatin 6mg/kg group, and IV group is GB-N group, and V group is GBCNH3(2.5mg/kg) group, VI group is GBCNH3(10mg/kg) group.High lipid food model control group is filled with and is fed distilled water while high lipid food of feeding, and fills with respectively for III, IV, V, VI group and feed required Simvastatin, GB-N, GBCNH3(2.5mg/kg while high lipid food of feeding), GBCNH3(10mg/kg).Wherein Simvastatin, GB-N are suspension (grinding preparation with 0.5% Xylo-Mucine CMC-Na), GBCNH3(2.5mg/kg), GBCNH3(10mg/kg) soluble in water.High lipid food amount of feeding is every 20g/ days.(grouping situation and each group dosage are in table 4)
Table 1 normal diet is fed 7 days rat serum total cholesterol (TC) content (unit mmol/L)
Table 2 is fed high lipid food 8 days rat serum total cholesterol (TC) content (unit mmol/L)
Note: eliminate underscore 12 mouse in above-mentioned table.
Table 3 rat is according to the horizontal random packet situation of TC (unit mmol/L)
Table 4 divides into groups situation and respectively organize dosage
| Group | Ⅰ | Ⅱ | Ⅲ | Ⅳ | Ⅴ | Ⅵ |
| Test medicine | Blank | High fat | Simvastatin | GB-N | GBCNH3 (low) | GBCNH3 (in) |
| Number of animals (only) | 10 | 10 | 10 | 10 | 10 | 10 |
| Dosage, mmol/kg | 0 | 0 | 0.0144 | 0.0366 | 0.0084 | 0.0337 |
| Dosage, mg/kg | 0 | 0 | 6 | 10 | 2.5 | 10 |
(3) Observe and measure and mathematical statistics method
Measure every day and record big white mouse body weight, each group is filled with by body weight and is fed administration 14 days, room temperature 22 DEG C, relative humidity 40-50 ﹪.After fasting in the 14th day is freely drunk water 16 hours, blood is got from aorta, place blood coagulation 30min, the centrifugal 15min separation of serum of 3000r/min, adopt enzymic colorimetric on full automatic biochemical apparatus, measure serum total cholesterol (TC) value, triglyceride level (TG) value, phospho-wolframic acid-magnesium precipitate method measures high density lipoprotein cholesterol (HDL) value and polyvinyel sulfate measures low density lipoprotein cholesterol (LDL) value.
Carry out statistical procedures to the data obtained, represent with mean ± standard deviation (x ± s), the significance of difference judges with T inspection.The computation of P value is: hyperlipidemia model group compares with blank group and obtains, and other to compare with hyperlipidemia model group by reagent group and obtain.(p<0.01 is pole significant difference, and p<0.05 is significant difference, and 0.05<p<1 is for there being effect trend there was no significant difference, and p>1 is retroaction)
(4) test philosophy
Enzymic colorimetric (CHOD-PAP) measures total cholesterol (TotalCholesterol, TC)
Temperature of reaction is 37 DEG C, first use CEH (CEH) that the cholesterol ester (CE) in serum is hydrolyzed to free cholesterol (FC) and lipid acid, use rCO (COD) that all FC in serum are oxidized to ch-4-alkene-3-ketone again, and produce H
2o
2, the latter and 4-AA (4-AAP) and 4-chlorophenol react (Trinder reacts) and generate red quinonimine, colorimetric estimation under 500nm wavelength under peroxidase (POD) acts on.
Enzyme measures triglyceride level (Triglycerides, TG) than method (GPO-PAP)
Temperature of reaction is 37 DEG C, lipoprotein lipase (LPL) is first used to be glycerine and lipid acid by the triglyceride hydrolysis in serum, under the effect of glycerol kinase (GK), glycerine and ATP reaction generate glycerol-3-phosphate and ADP, under the effect of GPO (GPO), glycerol-3-phosphate is oxidized by oxygen into phosphodihydroxyacetone and H
2o
2, under peroxidase (POD) effect, H
2o
2react (Trinder reacts) with 4-AA (4-AAP) and 4-chlorophenol and generate red quinonimine, colorimetric estimation under 500nm wavelength.
Polyvinyl sulfuric acid salt (PVS) Precipitation Determination low density lipoprotein cholesterol (LowDensityLipoproteinCholesterol, LDL-C)
LDL in serum can be precipitated by PVS, with aforesaid enzymatic assays serum TC with on the basis of this supernatant C h, deducts the latter, be LDL-C from the former, for promoting that LDL precipitation adds the only methyl ether of polyoxyethylene glycol (PEGME) in right amount.
Phospho-wolframic acid-magnesium precipitate method measures high density lipoprotein cholesterol (HighDensityLipoproteinCholesterol, HDL-C)
Low-density lipoprotein (LDL) in serum and vldl (VLDL) supernatant liquor after phospho-wolframic acid-magnesium precipitate are high-density lipoprotein (HDL) (HDL), its cholesterol level enzymatic assays.
(5) experimentation on animals test data
GB-N, GBCNH data to the evaluation test of hyperlipidemia model big white mouse blood fat list table 5-8 respectively in.Serum total cholesterol values measurement result is in table 5, and Triglyceride values measurement result is in table 6, and low density lipoprotein cholesterol pH-value determination pH the results are shown in Table 7, and high density lipoprotein cholesterol pH-value determination pH the results are shown in Table 8.
15th day big white mouse serum total cholesterol (TC) content (unit mmol/L) after table 5 administration
15th day big white mouse serum triglyceride (TG) content (unit mmol/L) after table 6 administration
15th day big white mouse serum LDL cholesterol (LDL) content (unit: mmol/L) after table 7 administration
15th day big white mouse serum High Density Lipoprotein Cholesterol (HDL) content (unit mmol/L) after table 8 administration
Note: remove the abnormal data with *
(6) lipid-lowering test result and comparative analysis
GB-N, GBCNH3 evaluation result to hyperlipidemia model big white mouse blood fat lists table 10-13 respectively in.To rat serum total cholesterol level measurement result analysis in table 9 and Fig. 7, divide in table 10 and Fig. 8 to rat serum content of triglyceride measurement result, to the interpretation of result of rat serum low density lipoprotein cholesterol assay in table 11 and Fig. 9, to the interpretation of result of rat serum high density lipoprotein cholesterol assay in table 12 and Figure 10.
Effect to rat serum total cholesterol TC:
Rat serum TC shows, and (see table 9 and Fig. 7) each group compare II group (hyperlipidemia model control group) has and reduce total cholesterol effect.III group (Simvastatin 6mg/kg), IV group (GB-N), V group (GBCNH3 is low), VI group (in GBCNH3) have pole significant difference.
The interpretation of result of table 9 rat serum total cholesterol (TC) assay
| Group | Number of animals | Total cholesterol value | P value |
| I, blank group | 10 | 2.35±0.33 | 2.12E-13 |
| II, hyperlipidemia model group | 10 | 25.06±3.74 | — |
| III, Simvastatin | 10 | 11.55±2.09 | 9.46E-09 |
| Ⅳ,GB-N | 10 | 10.22±2.17 | 2.50E-09 |
| V, GBCNH3 is low | 10 | 8.72±1.97 | 3.75E-10 |
| In VI, GBCNH3 | 10 | 8.17±2.03 | 2.46E-10 |
Note: P value refers to that each group is compared with II group: P < 0.05, and there were significant differences; P < 0.01, has pole significant difference.
Effect to rat serum triglyceride level TG:
Rat serum TG shows (see table 10 and Fig. 8), and by making comparisons with II group (hyperlipidemia model control group), each group has the effect of reduction triglyceride level.III group (Simvastatin 6mg/kg), IV group (GB-N), V group (GBCNH3 is low), VI group (in GBCNH3) have pole significant difference.
Table 10 rat serum triglyceride level (TG) assay interpretation of result (unit mmol/L)
| Group | Number of animals | Triglyceride values | P value |
| I, blank group | 10 | 0.56±0.10 | 1.53E-05 |
| II, hyperlipidemia model group | 10 | 2.179±0.87 | — |
| III, Simvastatin | 10 | 0.57±0.068 | 1.50E-05 |
| Ⅳ,GB-N | 10 | 0.57±0.11 | 1.69E-05 |
| V, GBCNH3 is low | 10 | 0.56±0.15 | 1.74E-05 |
| In VI, GBCNH3 | 10 | 0.55±0.098 | 1.40E-05 |
Note: P value refers to that each group is compared with II group: P < 0.05, and there were significant differences; P < 0.01, has pole significant difference.
Effect to rat serum low density lipoprotein cholesterol LDL-C:
Rat serum LDL-C result shows (see table 11 and Fig. 9), and by making comparisons with II group (hyperlipidemia model control group), each group has the effect reducing rat serum low density lipoprotein cholesterol.III group (Simvastatin 6mg/kg), IV group (GB-N), V group (GBCNH3 is low), VI group (in GBCNH3) have pole significant difference.
Table 11 rat serum low density lipoprotein cholesterol (LDL-C) assay interpretation of result (unit mmol/L)
| Group | Number of animals | Low density lipoprotein cholesterol | P value |
| I, blank group | 10 | 1.23±0.51 | 1.21E-08 |
| II, hyperlipidemia model group | 10 | 6.00±1.45 | — |
| III, Simvastatin | 10 | 3.58±0.63 | 0.00014 |
| Ⅳ,GB-N | 10 | 2.64±0.55 | 2.06E-06 |
| V, GBCNH3 is low | 10 | 3.48±0.76 | 0.00013 |
| In VI, GBCNH3 | 10 | 2.97±0.86 | 2.28E-05 |
Note: P value refers to that each group is compared with II group: P < 0.05, and there were significant differences; P < 0.01, has pole significant difference.
Effect to rat serum high density lipoprotein cholesterol HDL-C:
HDL-C result shows (see table 12 and Figure 10), by making comparisons with II group (hyperlipidemia model control group) (removing improper data), each group has the effect of high density lipoprotein increasing cholesterol wherein, and V group (GBCNH3 is low), VI group (in GBCNH3) have pole significant difference.
Table 12 rat serum high density lipoprotein cholesterol (HDL-C) assay interpretation of result (unit mmol/L)
| Group | Number of animals | High density lipoprotein cholesterol | P value |
| I, blank group | 10 | 0.65±0.17 | 6.64E-06 |
| II, hyperlipidemia model group | 10 | 0.27±0.041 | — |
| III, Simvastatin | 10 | 0.33±0.086 | 0.11 |
| Ⅳ,GB-N | 10 | 0.45±0.20 | 0.016 |
| V, GBCNH3 is low | 10 | 0.38±0.092 | 0.0060 |
| In VI, GBCNH3 | 10 | 0.54±0.20 | 0.0015 |
Note: P value refers to that each group is compared with II group: P < 0.05, and there were significant differences; P < 0.01, has pole significant difference.
(7) test-results and conclusion
In reduction total cholesterol, experimental result shows all there is pole significant difference between GB-N, GBCNH3 and hyperlipidemia model control group.And it is more remarkable that GBCNH3 respectively organizes the effect for the treatment of high total cholesterol.
In reduction triglyceride level, GB-N, GBCNH3 group and hyperlipidemia model control group have pole significant difference.GBCNH3 respectively organizes treatment high triglyceride Be very effective.
In reduction low-density lipoprotein, GBCNH3 group has pole significant difference compared with hyperlipidemia model control group.It is fairly obvious that this shows that GBCNH3 treatment low-density lipoprotein increases action effect.
In the reduction for the treatment of high-density lipoprotein (HDL), GBCNH3 group has pole significant difference compared with hyperlipidemia model control group, and this shows that GBCNH3 can treat high density lipoprotein cholesterol and reduce Be very effective.
In a word, GBCNH3 has regulating blood lipid action.
In sum; these are only preferred embodiment of the present invention, be not intended to limit protection scope of the present invention, therefore; all any amendments done within the spirit and principles in the present invention, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (8)
1. N-ethylenediamine base-piperonyl Pentadienamide hydrochloride, its chemical structure is:
2. one kind comprises medicinal compositions or the protective foods of N-ethylenediamine base described in claim 1-piperonyl Pentadienamide hydrochloride.
3. the preparation method of N-ethylenediamine base described in claim 1-piperonyl Pentadienamide hydrochloride, comprises piperinic acid and SOCl
2occur acylation reaction, then with H
2n-R reacts thus obtains N-ethylenediamine base-piperonyl Pentadienamide, and wherein, radicals R is 2-amino-ethyl.
4. N-ethylenediamine base described in claim 1-piperonyl Pentadienamide hydrochloride is preparing the application in blood lipid-lowering medicine or healthcare products.
5. the application of N-ethylenediamine base described in claim 1-piperonyl Pentadienamide hydrochloride in the medicine or healthcare products of preparation reduction serum total cholesterol.
6. the application of N-ethylenediamine base described in claim 1-piperonyl Pentadienamide hydrochloride in the medicine or healthcare products of preparation reduction low density lipoprotein cholesterol.
7. the application of N-ethylenediamine base described in claim 1-piperonyl Pentadienamide hydrochloride in the medicine or healthcare products of the reduction of preparation prevention high density lipoprotein cholesterol.
8. the application of N-ethylenediamine base described in claim 1-piperonyl Pentadienamide hydrochloride in the medicine or healthcare products of preparation reduction triglyceride level.
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